Exogenous control of cardiac gene therapy

Evidence of regulated myocardial transgene expression after adenovirus and adeno-associated virus transfer of expression cassettes containing corticosteroid response element promoters

L. Y. Lee, X. Zhou, D. R. Polce, T. El-Sawy, S. R. Patel, G. D. Thakker, K. Narumi, Ronald Crystal, T. K. Rosengart

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Objective: Because of the relative inaccessibility of the heart for repeated gene therapy, it would be useful to regulate the expression of transgenes delivered in a single dose of a gene therapy vector. Incorporation into the vector of a regulatable promoter that is responsive to pharmacologic agents that are widely used and well tolerated in clinical practice represents such a control strategy. Methods: A replication-deficient adenovirus or an adeno-associated virus containing a chimeric promoter composed of 5 glucocorticoid response elements and the murine thrombopoietin complementary DNA (AdGRE.mTPO or AAVGRE.mTPO) was administered to the hearts of Sprague-Dawley rats. Platelet levels were evaluated as a reporter of transgene activity with or without dexamethasone. For comparison, rats received a control adenovirus vector, AdCMV.mTPO or AdCMV.Null, and the control adeno-associated virus vector AAVCMV.luc, which encodes for the firefly luciferase (luc) gene. Results: Platelet elevation in the AdGRE.mTPO group peaked 4 days after dexamethasone administration, with a return to baseline 1 week after the initial corticosteroid dose. Subsequent dexamethasone administration at 2 and 4 weeks resulted in similar but progressively decreased responses. The AAVGRE.mTPO group had 5 peak platelet levels to a minimum of 2.2-fold with respect to baseline without diminution with subsequent dexamethasone administrations out to 169 days. In contrast, the AdCMV.Null and AAVCMV.luc groups demonstrated no increase in platelet counts and the AdCMV.mTPO group demonstrated a slow rise to a single peak platelet count independent of dexamethasone administration. Conclusion: It may be possible to control on demand the expression of a gene transferred to the heart. This strategy should be useful in cardiac gene therapy.

Original languageEnglish
Pages (from-to)26-34
Number of pages9
JournalJournal of Thoracic and Cardiovascular Surgery
Volume118
Issue number1
DOIs
Publication statusPublished - 1 Jan 1999
Externally publishedYes

Fingerprint

Dependovirus
Response Elements
Transgenes
Adenoviridae
Genetic Therapy
Dexamethasone
Adrenal Cortex Hormones
Blood Platelets
Luciferases
Platelet Count
Firefly Luciferases
Thrombopoietin
Glucocorticoids
Sprague Dawley Rats
Complementary DNA
Gene Expression
Genes

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

Exogenous control of cardiac gene therapy : Evidence of regulated myocardial transgene expression after adenovirus and adeno-associated virus transfer of expression cassettes containing corticosteroid response element promoters. / Lee, L. Y.; Zhou, X.; Polce, D. R.; El-Sawy, T.; Patel, S. R.; Thakker, G. D.; Narumi, K.; Crystal, Ronald; Rosengart, T. K.

In: Journal of Thoracic and Cardiovascular Surgery, Vol. 118, No. 1, 01.01.1999, p. 26-34.

Research output: Contribution to journalArticle

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AU - Patel, S. R.

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